Project Summary A novel pneumonia caused by a previously unknown betacoronavirus emerged in Wuhan, China, in December 2019. The virus is closely related to the severe acute respiratory syndrome coronavirus (SARS CoV-1), which led to an outbreak in 2003, and has been named SARS-CoV-2. The human disease caused by SARS-CoV-2 is called COVID-19. During the current SARS-CoV-2 outbreak, the incidence of known cases has rapidly increased such that, on January 5, 2020, there were 59 confirmed cases, 278 cases on January 20, 2118 cases on January 26, and more than 80,000 cases and 2700 deaths as of February 25, 2020, according to various international health reporting agencies. As a result, on January 30, 2020, the International Health Regulations Emergency Committee of the World Health Organization (WHO) declared the COVID-19 outbreak a Public Health Emergency of International Concern. On January 31, 2020, the US Department of Health and Human Services declared a public health emergency in the United States. As of March 21, 2020, there are 297,090 cases of COVID-19, including 22,177 cases in the United States (US), resulting in a total of 12,755 deaths globally. Despite quarantine measures, SARS-CoV-2 continues to spread (1). Outbreak forecasting and modeling suggest that these numbers will continue to rise (2). At present, there is no specific antiviral therapy for COVID-19. Few treatment studies have been conducted because most human CoV strains cause self-limited disease, and care is supportive. After SARS-CoV-1 was identified in 2002-2003 and caused a large global outbreak, there was an increased interest in the development of specific therapeutic agents. SARS-CoV-1 patients were treated with corticosteroids, type 1 IFN agents, convalescent plasma, ribavirin, and lopinavir or ritonavir; except for ribavirin, many of these agents have in vitro pre-clinical data that support their efficacy (3-11). Since the SARS-CoV-1 outbreak in 2002-2003, new therapeutic agents targeting viral entry proteins, proteases, polymerases, and methyltransferases have been tested; however, none of them has been shown to be efficacious in clinical trials (12-19). Given the lack of specific antiviral therapy for SARS-CoV-2 infection, and the known safety profiles and ready availability of HCQ and Azithro as potential antiviral agents, based on pre-clinical and small clinical studies, this randomized, placebo-controlled trial will evaluate the efficacy and safety of HCQ and Azithro in persons who have active SARS-CoV-2 infection and mild to moderate COVID-19 symptoms.